Most cases of Hepatosplenic T-cell lymphoma (HSTCL) are derived from gamma delta T-cells and exhibit an immature cytotoxic phenotype. Cytogenetic studies from our group and others indicated a high frequency of nonrandom chromosomal abnormalities including isochromosome 7q. However, the specific genes responsible for neoplastic transformation had not been identified. STAT5 activation has been linked to T-cell development and homeostasis, as well as to the initiation of gamma delta T-cell differentiation. Deregulation of the STAT3 pathway has been reported in a number of T-cell malignancies. We reasoned that these genes could potentially play a role in hepatosplenic T-cell lymphomas. (Nicolae, Xi et al. 2014) Twenty-one cases of HSTCL with suitable FFPE material for analysis were identified from our archive. In collaboration with Dr. Mark Raffeld, targeted analysis for STAT3 and STAT5B mutations was performed. 9/21 HTSCL cases (42.8%) contained STAT mutations. The high frequency of STAT5B and STAT3 mutations in HSTCL strongly suggests that deregulation of the STAT pathway is an important oncogenic event in the pathogenesis of this lymphoma. Lymphomatoid granulomatosis (LYG) is a rare angiocentric and angiodestructive EBV-associated B-cell lymphoproliferative disorder. We recently completed a comprehensive review of the pathological specimens for patients entered on the NCI clinical protocol.(Song, Pittaluga et al. 2015) Sixty-nine patients were initially referred as possible LYG, with 14 cases excluded based on pathological review at the NIH. Of the 55 patients that were included in the study, 34 of the patients (62%) had prior therapy before enrolling in the LYG clinical trial, while 19 patients (35%) did not, and for 2 patients it was unknown whether there was prior treatment (4%). For the patients that had prior treatment, both the pre and post therapy biopsies were reviewed. We employed a grading system initially developed at the NCI; 30% were grade 1, 22% were grade 2 (22%), and 48% grade 3. B-cell clonality by PCR correlated with histological grade. However, necrosis could be found in all histological grades. Most patients who develop LYG do not have any overt evidence of immunodeficiency, although some patients exhibit low levels of CD8+ T-cells.(Dunleavy, Chattopadhyay et al. 2010) Therefore, the underlying pathogenesis for the inability to control EBV in this disease is unknown. As such, we attempted to assess the immune microenvironment in the LYG lesions. Regulatory T cells (Tregs) are characterized by a specific phenotype (CD4+CD25+ FOXP3+) and have been shown to suppress tumor-specific T-cell immunity in the tumor cell microenvironment. We performed FOXP3 immunostaining and found that there were more FOXP3-positive T cells in LYG grade 3 (median 39/10 hpfs) versus grades 1 or 2 (median 18/10 hpfs) suggesting that an increased number of Tregs in grade 3 may contribute to disease progression. These studies help illuminate the nature of the immune defect in LYG. We showed that EBV may be expressed in the lymphocyte-predominant (LP) cells of nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) in both children and adults.(Huppmann, Nicolae et al. 2014) The conventional wisdom had been that NLPHL is negative for EBV, while classical Hodgkin's lymphoma (CHL) is positive in 15-25% of cases. A single study from Vietnam reported cases of NLPHL positive for EBV.(Chang, Khen et al. 2005) It was unknown if this finding was restricted to Asian cases, or could also be seen in Western populations. Therefore, we coordinated a large collaborative study involving three North American centers (NIH, Massachusetts General Hospital, and the British Columbia Cancer Agency), to analyze 302 cases of NLPHL, 145 in pediatric patients and 157 in adults. Five (3.4%) pediatric and 7 (4.5%) adult NLPHL cases contained EBV(+) LP cells. No differences in clinical outcome were observed, although given the retrospective nature of the study, clinical data was limited. However, we can conclude that EBV-positivity does not exclude a diagnosis of NLPHL. EBV-positive diffuse large B-cell lymphoma of the elderly (DLBCL-E), first described by Oyama et al. was included in the 2008 WHO classification as a provisional entity. It was defined as an aggressive EBV positive monoclonal B-cell proliferation arising in patients 50 years of age, in the absence of recognized immunodeficiency or iatrogenic immunosuppression. Senescence of the immune system inherent to the aging process leading to defective surveillance of EBV was thought to play a major role in pathogenesis. In recent work , we described 46 cases of EBV+ diffuse large B-cell lymphomas (DLBCL) in patients less than 45 years of age with no significant prior history or identifiable causes of immunosuppression.(Nicolae, Pittaluga et al. 2015) We showed that EBV+ DLBCL in young patients resemble the disease seen in older patients in many respects. They had an ABC/non-GCB immunophenotype and nearly all were EBV latency type II. The disease affected predominantly males (M:F = 3.6:1), with a median age of 23 years (range, 4-45 years). There was a significant peak in incidence in the third decade. Interestingly, all patients presented with lymphadenopathy and only 11% had extranodal disease. The presence of primarily nodal disease differs from EBV+ DLBCL as seen in the elderly, which is more often extranodal. Additionally, most patients responded to standard treatment and had a favorable outcome. With a median follow-up of 22 months, 82% of patients are in clinical remission and only 8% died of disease. A major question is what factors contribute to lymphoma pathogenesis in this population of young patients without evident underlying immunodeficiency. We found that EBV+ DLBCL in young patients showed dysregulation of immune checkpoints, indoleamine 2,3-dioxygenase (IDO) and the PD1/PD-L1 axis with promotion of an inhibitory, tolerogenic immune environment. Most of the analyzed cases showed PD-L1 positivity of the tumor cells and high expression of PD-L1 and IDO in the histiocytic/dendritic cell microenvironment. Therefore, it is likely that PD-L1 presence on tumor cells together with high expression of IDO and PD-L1 in the tumor microenvironment promotes immune escape of EBV-transformed B-cells. Chang, K.-C., N. T. Khen, et al. (2005). Epstein-Barr virus is associated with all histological subtypes of Hodgkin lymphoma in Vietnamese children with special emphasis on the entity of lymphocyte predominance subtype. Human Pathology 36(7): 747-755. Dunleavy, K., P. Chattopadhyay, et al. (2010). Immune Characteristics Associated with Lymphomatoid Granulomatosis and Outcome Following Treatment with Interferon-Alpha. Blood 116(21): 424-424. Huppmann, A. R., A. Nicolae, et al. (2014). EBV may be expressed in the LP cells of nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) in both children and adults. Am J Surg Pathol 38(3): 316-324. Nicolae, A., S. Pittaluga, et al. (2015). EBV positive large B cell lymphomas in young patients: a nodal lymphoma with evidence for a tolerogenic immune environment. Blood. Nicolae, A., L. Xi, et al. (2014). Frequent STAT5B mutations in gammadelta hepatosplenic T-cell lymphomas. Leukemia 28(11): 2244-2248. Song, J. Y., S. Pittaluga, et al. (2015). Lymphomatoid granulomatosis--a single institute experience: pathologic findings and clinical correlations. Am J Surg Pathol 39(2): 141-156.